The past twenty years have seen an explosion of interest in the structure and function of RNA and DNA. We now know that while some 80% of the human genome is transcribed into RNA, just 3% of those transcripts code for protein sequences. Noncoding RNAs and DNAs have been demonstrated to regulate gene expression and other biological regulatory processes. The deregulation of these RNAs is now known to be causative in a variety of human diseases, ranging from cancer to bacterial and viral infection. However, efforts to target RNA and DNA with small molecules have lagged far behind protein targets. Our group's efforts to target RNA and DNA with druglike small molecules is based around using a Small Molecule Microarray (SMM) screening platform. We have assembled a library of 65,000 small molecules that may be screened in the microarray format. In each case, molecules are printed on to glass slides using a microarrayer robot and covalently linked to the surface. Next, fluorescently labeled oligonucleotides with defined structures (such as hairpins or quadruplexes) are incubated on array surfaces. Spots that increase in fluorescence intensity are scored as binding. Once hit molecules of interest are identified from the screen, they are characterized through chemical synthesis, biochemical and biophysical analyses, and if possible in cellular assays to confirm biological activity as well as binding to the oligonucleotide. By rapidly screening a variety of diverse folded nucleic acids targets such as G-quadruplexes, hairpins, triplexes, pseudoknots, i-motifs, and 3-way junctions, it is possible to identify selective small molecule hits suitable for further study. Furthermore, structural approaches including biomolecular NMR and X-Ray crystallography using hits from SMM screens highlight the potential for structure-guided design on RNA and DNA related to cancer and infectious disease. A major focus of this project is developing structure-based approaches for developing small ligands that target DNA and RNA.